19-lower-alkyl-10alpha-derivatives of cortical hormones



United States Patent 0 N0 Drawing. Filed Mar. 1, 1963, Ser. No. 262,234 21 Claims. (Cl. 260-23955) The present invention relates to novel cyclopentano- 'phenanthrene compounds and to a process for the production thereof.

More particularly the present invention relates to 19- lower-alkyl-lOct-derivatives of cortical hormones.

The novel compounds of the present invention are represented by the following formulas:

In the above formulas X represents a lower alkyl group; W represents a double bond or a saturated linkage between C1 and C2; Z represents hydrogen, methyl, fluorine or chlorine, all having a or ,8 configurations; Q represents a fl-hydroxyl or a keto group; Y represents hydrogen, fluorine or chlorine; R represents a hydroxyl group; T represents tie-hydrogen, a-acyloxy, a-m'ethyl or ,B-methyl; T and R together represent the group in the 160:, 170t-pOSitiOI1S, wherein R and R each represents hydrogen or a hydrocarbon residue of up to 8 carbon atoms of straight, branched, saturated or unsaturated, cyclic or mixed aliphatic cyclic chain, or aromatic, such as methyl, ethyl, isopropyl, phenyl, toluyl, methyl-cyclohexyl and the like; R represents hydrogen or a hydrocarbon carboxylic acyl group of less than 12 carbon atoms.

The acyl groups are derived from hydrocarbon carboxylic acids containingles-s than 12 carbon atoms which may be saturated or unsaturated, of straight, branched, cyclic or cyclic-aliphatic chain, aromatic and may be substituted by functional groups such as hydroxy, alkoxy containing up to 5 carbon atoms, acyloxy containing up to 112. carbon atoms, nitro, amino or halogen. Typical ester groups are the acetate, propionate, enanthate, benzoate, trimethylacetate, phenoxyacetate, cyclopentylpropionate, aminoacetate, and fi- -ch-loropropionate.

The compounds represented by the above formulas are valuable cortical hormones with high anti-inflammatory, low catabolic, glycogenic and thymolytic activities. In

- addition, they are anti-androgenic, anti-gonadotrophic and anti-estrogenic hormones. Furthermore, they have high topical activity in skin disorders, such as psoriasis, allergic dermatitis and the like.

The novel compounds of the present invention are prepared by the process illustrated by the following formula scheme:

CH -OAO In the above formulas Q, X, Y, Z,R, R and T have'the same meaning as described hereinbefore.

In practicing the process outlined above, a 19-lower alkyl A -10a-pregnen-17a-ol-3,20-dione derivative obtainedin accordance Withmycopending US. patent application Serial No; 262,236, filed-March 1, l-963,'from the corresponding A -1Ou-pregnene-17a,19-diol-3,20-dione by protecting conventionally the keto groups in the form of ketals, oxidizing the ,19-hydroxy with chromium trioxide in pyridine to the 19-aldehyde, treating the latter with a lower alk'yl magnesium bromide, oxidizing the obtained :19-lower alkyl 19-hydroxy'steroid with chromium trioxide, subjecting the produced 19-lower alkyl-19-keto compound to the Wolfif-Kishner reaction, and finally hydrolyzing conventionally the ketal groups, is treated with, iodine in the presence of calcium oxide to give the corre sponding 21-iodo derivative, which upon treatment with potassium acetate in a suitable solvent, such as acetone, preferably at reflux temperature, affords thecorresponding 21-acetoxy 19 lower alkyl-A -1Oa-pregnene-17oq-ol-3,20- dione derivative (I). The latter 3,20-dione, upon reaction with ethyleneglycol in the presence of'p-toluenesulfonic acid yields the corresponding 3,20-bis-cycloethylenedioxy-19-lower-alkyl-A l Oa-pregnene l7oz,2 l -diol 21- acetate compoundflI), which is treated with an organic peracid, such as monoperphthalic acid, in an inert solvent, preferably chloroform, to produce the corresponding I lower alkyl 3 etho'xy-A -l oot-pregnadien17oc-ol-20-one derivatives, which upon reaction with approximately 1, molar equivalent of'N-chlorosuccinimide or another N- chloro amide or imide, in the presence of sodium acetate and acetic acid, yield the corresponding 6fl-chloro-l9 lower alkyl-A -l0u-pregnene-17a,2l-diol-3,20-dione '21- acetate derivatives (IV: Z:fl-chl orine; R '=acetyl).

The aforesaid Zl-acetoXy-lQ-lower alkyl -3-ethoxy-d 10b: pregnadien 17a ol ZO-one derivatives are treated with perchloryl fluoride in dimethylforniamide, 'to produce the corresponding 6,6-fiuoro-19-lower-alkyl-ni-ltlotpregnene 1705,21- diol 3,20 dione ZI-acetate derivatives (IV: Z=fi-fluorine;'R :Acetyl). The (Sci-halo compounds of the present invention (IV:

Z=ct-halogen) may also be obtained by treatment of the a corresponding 6fl-halo compounds (IVLZ=;3-ha1ogen) with hydrogen-chloride in acetic acid, or with another mixture with similar'acidity, 1

3, 20-bis-cycl-oethylenedioxy-Sa, 6a,-oxido-l9-l-ower alkyl- 1Oa-pregnene-1704,21-di0l' Zl-acetate (III).

OXy5a,6oc-OXid0 compound with methyl magnesiumbromide in an inert solvent such as ether or tetrahydrofuran, followed by conventional Working up and treatment of the residue -with a mineral acid, such as 8% sulfuric acid, and

thereafter with thi-onyl chloridein pyridine at about ---10 C, for approximately 4 minutes,,.there is obtained the latter 6,8-methyl derivative is treated with analkali metal hydroxide, such as sodium hydroxide, 'in a suit able. solvent, such as methanol, thus affording the corresponding 6owmethyl derivative (IV: Z'=a-methyl; R =H).

" When treating the '3,20-bis-cycloethylenedioxy-5ot,6a-

oxido compoundsflII) with'hydrogen chloride, in a suitable organic solvent, such as ethyl acetate, there are pro cluced. the corresponding 6e-chloro1l9-l0wer 211kyi-A -lOrx pregnene-l7a,2l diol 3,20 dione 21 acetate'derivatives Upon reaction of the 3,20-bis-cycloethylenedioxy-5a,6o;-

. oxido compounds (W) with anhydrous hydrogen fluoride, preferably in the presence of boron trifiuoride etherate, followed by treatment with hydrogen chloride, there V are produced the.corresponding6tx-fluoro-l9-lowerv alkyla A ltla-pregnene-l7a,2l diol 3,20-dione Zl -acetate deriva- Upon reaction of the latter 3,20-bis-cycloethylenedii The l9-lower alkyl-A -lOa-pregnene l7a,21-diol-3,20- dionederivatives, mentioned theretofore (I, IV) upon incubation with'adrenal glands in a suitableimediurm'eg. an aqueous solution of alkali metal phosphates'and chlorides and magnesium sulfate, mixed with, an aqueous solution of fumric acid and sodium hydroxide,'for a period of time of the order of 3 hours, atapproximately 28'-3 7 C., yield the corresponding 19-lower alkyl-A4-l0a-pregnenc-l1/3,l7a,2ltriol-3,20 dione dcrivatives (V).

The latter 11 ,B-alcohols (V) are treated with mesyl chloride in dimethylformamide and pyridine at approximately C. for about half an hour to produce the corresponding l9-lower alkyl-n e10a-pregnadiene-17a,21- 'diol-3,20-dione derivatives (VI). 7

The last named A -derivatives are treatedwith an Nbromo amide or imide, such as N-bromo zacetamide, in the presence of perchloric acid, in an inert solvent, as for example, dioxane, to give the corresponding A -9a-bromollB-alcohols which upon treatment with a mild base, such as potassium acetate in a suitable solvent, e. g.-acetone, preferably at reflux temperature,,aiford the corresponding 19-lower alkyd-9,8,1 l ,3 oxido.- A -1Oa pregnene 17 cz,2 l-diol- "3,20-dione compounds. 7 r r The latter 9,6,1lfl-oxido compounds, upon treatment with a hydrogen halide, such as, hydrogen fluoride. or

hydrogen chloride in a suitable inert organic solvent, e.g.,,

The 1l,8-hydroxyl group of the latter compounds and of the 9a-unsubstituted-11 8-alcohols (IV), after previous conventional protection of the 21-hydroxyl group (eg. by esterification, is oxidized preferably with Jones reagent (chromium'trioxide in sulfuric acid), thus affording the corresponding llv-ketones (VII: Q=O).

' The l9 -lower alkyll()a-.pr egnene-11,6,l7ct,2l-triol- 3,20-dione. and 19-lower aIkyI-Af -lOa-pregnene-17,21- dio1-3,11,20-trione derivatives (VII) upon'reaction with chloranil in terbutanol at reflux temperature, for approximately 8 hours, yields the corresponding A4 6 -derivatives (VIII). I o

The 19-lower alkyl-M-lOa-pregnenepderivatives represented by Formula VII are treated with'2,3- dichloro-'5,6-

dicyano-l,4 -b ?nzoquinone,*in a suitable solvent, such as V dioxane, preferably at reflux temperature for a period. of time 015 theorder of 10 hours, to produce the corresponding'iA pregnadiene derivatives ,(IX);

' When treating theVaforesaid A s-compounds (VIII) with 2,3-dichloro-5,6 dicyano l,4 benzoquirione under the same conditions "as described hereinbefore, there are obtained the corresponding=A -pregnatriene derivatives The compoundsof l7a'-ketonide grouping, yield the corresponding :,1765- diols by conventional treatment withzan acid, such as.

' acetic acid. The obtained'diols, upon conventional esteri:

fication in pyridine'with acylating agephas for ex;

the presentinventionhaving a 160i,- i

ample acetic anhydride or caproic anhydride, afford the corresponding 16-acylates.

The latter 16a,17 x-diols upon conventional condensation with a ketone or aldehyde, such as benzaldehyde, acetophenone, methyl ethyl ketone, acetone, and the like, in the presence of an acid, yield the corresponding 16cc,- 17a-methylenedioxy derivatives, wherein the substituents in the methylenedioxy group may be different from those of the previously hydrolyzed ketonide grouping.

The compounds of the present invention having a 21- acyloxy group, are saponified by conventional treatment with a base to produce the corresponding 21-free alcohols, which in turn, may be acylated conventionally in pyridine with an acylating agent to give the corresponding 21- acylates, wherein the acyl group may be different from the previously saponified one.

The following specific examples serve to illustrate the present invention, but are not intended to limit the scope thereof:

Example I A cooled solution of 4 g. of 19-methyl-A 1Oa-pregnen- 17oc-0l-3,20-di0116 (obtained according to my copending U.S. pat. appl. Ser. No. 262,236, filed March 1, 1963) in 30 cc. of tetrahydrofuran and 18 cc. of methanol was treated under continuous stirring with 6 g. of pure calcium oxide, in small portions, and then with 6 g. of iodine. The stirring was continued at room temperature until the solution turned pale yellow. The mixture was poured into ice water containing 18 cc. of acetic acid and 2 g. of sodium thiosulfate. After stirring for 15 minutes the solution was decanted and the precipitate was collected by filtration, thus giving the corresponding 21-iodo derivative. This compound was mixed with 80 cc. of acetone and 12 g. of recently fused potassium acetate and the mixture was refluxed for 8 hours, concentrated to a small volume, diluted with water and extracted with ethyl acetate; the extract was washed with water, dried over anhydrous sodium sulfate and concentrated until crystallization started. The precipitate was collected and crystallized from methanol-water, thus yielding 19-methyl- A -10u-pregnene-t17u,21-diol-3,20-dione 21-acetate (Cpd. No. 1).

Following the same procedure, the starting compounds listed under A (obtained in accordance with the aforesaid patent application), were converted into the corresponding products set forth under B.

A nd.

19-methyl-16a,17a-lsopropyli- 2 19-methyl-lfia-lm-isopropylidcnedioxy-N-lOa-pregnenedenedi0xy-A -10a-pregnen- 3,20-dione. 2l-0l-3,20-dione acetate. 16a,19-dimethyLA -1Oa-pregnen- 3 16a,19-dimethy1-A -10a-pregnene-17a,21-di0l-3,20-dione 21-acctate.

16H,19-dimethyl-A -10wpregnene-17a,21-di0l-3,20-dlono ZI-acetate.

17a-ol-3,20-dione.

methyl-16w,17a-isopropylidene- 5 19-ethyl 16a,17a-isopropylidioxy-A -wpregnene-3,20- denedioxy-A -lfla-pregnendione. 21-ol-3,20-di0ne acetate. 19-ethyl-A -10a-pregnen-17a-o1- 6 1Q-ethyl-A -1Oa pIegnen-I7a,

3,20 dione. 21-diol-3,20-d1one ZI-acetato lfia-methyl-lg-ethyl-A -10a- 7 16a-methyl-19ethyl-A -l0apregnen-l7a-ol-3,20-dione. pregnen-17a,21-diol-3,20-

3,20-dione 21-acetate. ltifl-methyl-l ethyl-A -wa- 8 1tie-mothyl-lQ-ethyl-M-lflapregnen-17a-ol-3,20-di0ne.

dione ZI-acetate.

7 Example 11 formed during the reaction. Aqueous sodium bicarbonate solution was added to the cooled mixture and the organic phase was separated, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue crystallized from acetone-hexane to give 3,20- bis-cycloethylenedioxy 19 methyl A IOa-pregnene- 17a,21-dio1 21-acetate (Cpd. No. 9).

The compounds Nos. 2 to 8, inclusive, were treated by the above procedure, thus afiording' respectively:

Cpd. No.:

10. 3,20-biscycloethylenedioxy-19-methy1 16a,17a-

isopropylidenedioxy-A -lOa-pregnen-Zl-ol acetate. 11. 3,ZO-biscycloethylenedioxy16a,19-dimethyl A tlOu-pregnene-17a,21-diol 21-acetate. 12. 3,20-biscycloethylenedioxy-16,8,19-dimethyl A 10u-pregnene17a,21-diol ZI-acetate.

13. 3,ZO-biscycloethylenedioxy-19-ethyl-16u,17aisopropy1idenedioxy-A -1Oa-pregnen-Zl-ol acetate. 14. 3,ZO-biscycloethylenedioxy-19-ethyl-A -10oa-pregnene-17a,21-diol 21-acetate.

15. 3,20 biscycloethylenedioxy 16oz methyl 19- ethyl-A -10a-pregnene-17a,21-diol ZI-acetate.

16. 3,20 biscycloethylenedioxy 16/3 methyl-19- ethyl-A -10a-pregnene-17a,2l-diol 21-acetate.

Example III A solution of 2.5 g. of 3,20-biscycloethylenedioxy-19- methyl-A -10ot-pregnene-17a,21-diol 21-acetate (Cpd. No. 9) in cc. of chloroform was cooled to 0 C. and mixed with 1.1 molar equivalents of monoperphthalic acid in ether solution. The mixture was kept at room temperature for 20 hours, diluted with water, the organic layer was separated, washed with aqueous sodium bicarbonate solution and then with water to neutral, dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization from acetone-hexane gave 3,20'-biscycloethylenedioxy-19-methy1 5a,6a oxido 10oz pregnane- 17oc,21-di'ol 21-acetate (Cpd. No. 17).

The compounds Nos. 10 to 16, inclusive, were treated by the above procedure, thus atfording respectively:

Cpd. No.:

18. 3,ZO-biscyc]oethylenedioxy-19-methy1 16oc,17uisopropylidenedioxy-Su,6 xoxido-IOu-pregnan 21- 01 acetate.

19. 3,20 biscycloethylenedioxy 16a,19 dimethyl- 5a,6a-oxido-10a-pregnane-17a,2l-diol 21--acetate.

20. 3,20 biscycloethylenedioxy 16 8,19 dimethyl- 5u,6a-oxido-10a-pregnane-17a,21-diol 21 acetate.

21. 3,20-biscycloethylenedioxy 19 ethyl-16a,17o:- isopropylidenedioxy-S0:,6u-0Xid0-lOa-pregnan 21- 01 acetate.

22. 3,20-biscycloethylenedioxy 19-ethyl-5a,6u-oxido- 10a-pregnane-17a,21-diol-21-acetate.

23. 3,20-biscycloethylenedioxy 16a methyl 19- 6a,6a-'oxido-10a-pregnane-17a,21-diol 21 acetate. acetate. V

.24. 3,ZO-biscycloethylenedioxy 16,8 methyl 19- ethyl-5u,6a-oxido-IOa-pregnane :,21 diol 21- acetate. 7

Example IV.

To a solution of 40 cc. of 4 N methylmagnesium bromide in ether was added, with stirring, a solution of 2 g. of 3,ZO-biscycloethylenedioxy-19-methyl-5a,6oc-oxido-10apregnane 170:,21-di0l 21-acetate (Cpd. No. 17) in 60 cc. of dry tetrahydrofuran and the stirred mixture heated under reflux for 30 minutes. The condenser was then replaced by a calcium chloride tube, the ether allowed to boil off and When'the internal temperature reached 54 C, the condenser was readapted and the mixture refluxed for an additional 4 hours. 400 cc. of a saturated solution of ammonium chloride was added slowly to the cooled mixture which was then stirred for 15 minutes before transfer.

. '7 to a separatory funnel. The tetrahydrofuran layer Was separated, dried and evaporated to dryness.

A solution of the resulting residue in 70' cc. of methanol and 7-cc. of 8% aqueous sulfuric acid was refluxed for a 40 minutes. It was then neutralized with saturated sodium carbonate solution, concentrated to ca. 20 co. in vacuo and poured into Water. The formed precipitate was filtered oif, washed thoroughly with water and dried.

A solution of thedry precipitate in'7 cc. of dry pyridine was cooled to 10 C, treated with 0.4 cc. of thionyl chloride and the mixture allowed to stand for 4 minutes at this temperature. Ice-water was added and the crystalline precipitate was filtered, washed and dried, yielding 6,8,19-dimetl1yl-A -lOu-pregnene 1Za,2l-diol-.3,20-dione (Cpd..No.

' The compounds Nos. 18 to 24,. inclusive, were treated by the. above method, thus affording respectively:

Cpd. No.:

26. 6fl,l9 dimethyl l6 x,17a isopropylidenedioxy- A -IOa-pregnen-Z1-ol-3,20-dione. e 27. 6fi,'16a,19 a trimethyl A -l0a pregnene-17u,21-

diol-3,20-dione. A

. 28. 65,16 3,19-trimethyl-A -10a'- pregnene 1706,21-

- diol-3,20-'dione.

29. 6,8-methyl-l9-ethyl-16a, 17 u-"isopropylidenediox A -lOu-pregnen-Z1-ol-3,20-dione. 30."GB-methyl-19-ethyl-M-1Ooc pregnene 1704,21- dio1-3 ,ZO-dione.

31. 6fl,16a-dimethyl-19-ethyl A 400: pregnene-- 17a,2l-di0l-3,20-dione. 32. 66,;16fl dimethyl-1-9-ethyl-A -10u-pregnene-17oc,

21-diol- 3,20-dione.

Example 1/ 1 g. of 6,8,19-dimethyl-M-lfld-pregnene-lhll-diol V 3,20-di0ne (Cpd. No. 25) was dissolved in 20', cc. of

neutrality and dried. Recyrst'allization from methylene chloride afforded 6 oz-chloro- 1 9-methyl o 1 Oar-pregnene- 17oc,2l-diol-3,20-.dione 21-acetate (Cpd. No. 41). p

The compounds Nos. 18 to 24, inclusive, were treated by the above method, thus affording respectivelyr Cpd. No.:

42. 60L-Ch1OI'O-19-I1'1Cthy1 16IX,1706 isopropylidenedioXy-A -IOa-pIegnen-Z1-ol-3,2O-dione acetate.

43. 6or-chloro-l6a,l9-dimethyl A -1Qoc' pregnene- 17a,21-dio1-3,20-dione .21-acetate.

44. 6a chloro-16,8,l9-dimethyl A IOm-pregnene- 17a,21-diol-3,20-dione ZI-acetate. V V

45; 6or-chloro-19-ethyl 1605,17oc isopropylidenedioXy-A -10a pregnen-21-ol-3,20-dione acetate.

46. 6or-chloro-l9-ethyl-A -lOa-pregnene l7oc,21di0l- 3,20-dione ZI-acetate. p 7

47 6a-chloro 16a-methyl-19-ethyl-A =l0a-pregnene- 17a-21-diol-3,20-dione ZI-acetate;

48. 6a-chloro-16B methyl- 19-ethyl-A -l0a-pregnenel7oz,21 dio1-3,20-dione 21- acetate.

Example VII 2.8 cc. of boron trifiuoride. etherate was slowly added with stirring to 220 mg. of anhydrous hydrogen fluoride cooled in an acetone-Dry Ice bath. 7

To a solution of 1 .g. of compoundNo. 17 .in 16' cc. of ,a mixture of equal parts of benzene and etherwas added 1.3 cc. of the fluoroooric acidreagent. The mixture was kept for 3 hours. at room temperature, then washed four times with water, dried .over anhydrous methanol containing 0.2 g. of sodium hydroxide and'the mixture was kept for one and a half hours at room temperature, then poured into water and extracted with.

methylene chloride. Evaporation of the methylene chloride solution and crystallization of the 'residuefrom acetone-hexane yielded :6a,19-dimethyl-A- -1Oa pregnene- 17a,2l-diol-3,20-dione (Cpd. No. 3).

The compounds Nos. 26 to 32, inclusive, were treated by the above method, thus afiording respectively;

Cpd. No;

34. 6a, l9-dimethyl 160:,l7a isopropylidenedioxw A 1 Owpregnen-Z 1-ol-3 ,ZO-dione.

35. 6m,16u,19-trimethyl A 10a-pregnene-112a,21- f diol-3,20-dione. 36. 6a,16fi,19-trimethyl A 10a-pregnene-17a,2l-

diol-3,20-dione.

V dioxy-At -lOa-pregnen-Zl-ol-3,20-dione.

38. 6u-methyl-19-ethyl A 10a -pregnene- 17a,21-

i I diol-3,20-dione. r

'39. 6a,l6a-dimethyl-19-ethyl-A -10oa pregnene-17o'c,-,

21-diol-3,2O-dione. 40. 6a,16fi-dirnethyl-l9-- ethyl At-lOa pregnene- 17u,21-diol-3,20-dione.

Example VI 'Into a suspension of 1 gl'of 3,20-biscycloethylenedioxy-- acetate ,(CpckNo. 17) in cc. of glacial aceti'cacidnvas passeda slow stream. of dry hydrogenlchloride; after 10 minutes all the solid'material was dissolved. The gas was passedxthrough the reaction mixture for a roar of 5 hours: The solution was concentrated to about onethird its initial volume by distillationunderreducedpres sure at 35 C., then it was poured into ice-water, The

precipitate formed was col1ected,;.washed with waterito" (sov sodium sulfate and the solvent evaporated under reduced pressure.

drogen chloride. The gas was passed through the reaction mixture for a total of 5 hours. The solution was then Washed abundantlywith water, dried and evaporated to dryness. Thev residue; was washed with water to neutrality and dried. Recrystallization from methylone chloride-hexane afio'rded .6cr-fiuoro 19-methyl-A -10apregnene-l7a,21-diol-3,20-dione 21-acetate (Cpd. No.

1 The compounds Nos. l8 to 24, inclusive, were treated by the abovemethod, thus affording respectively: 7

' Example VIII V A suspension of' 5 g. of 19-n1ethyl-A -lOor-pregnene-.

17a,2l-diol-3,20 dione ZI-acetateKCpd. No. 1) in 37.5 cc. of anhydrous peroYide-frec dioxane, wastreatedwith 6.2 c c.'of freshly distilled ethyl orthoformate and 2.5 g.

of. p-toulenesulfonic acid. The:.;m ixture' was stirred at roomtemp'erature'for 1 5 minutes and the resulting solu- V ti'onlet stand for130minutesfurther. '4 ccfofpyridine- V The formed precipitate was collected by filtration,- water Washed and air dried; Re crystallization from acetone-hexane afforded '3-et-hoxy- 19-'methyl.-A?' -1Ompregnadiene-lj zl1 Y diol-ZO-bne 21- acetatetCpd.1N0. 57). 7 "I were added and then water.

The residue Was suspended in 40 cc. of ethyl acetate and there was passed a slow stream of dry hy- By the same procedure, there were treated the compounds Nos. 2 to 8, inclusive, thus yielding respectively:

Cpd. No.:

58. 3-ethoxy-19-methyl-16a,17a-isopropylidenedioxy-A -10a-pregnadien-21-ol-20-one acetate. 59. 3-ethoxy-16a,19-dimethyl-A -lOa-pregnadiene- 17a,21-diol-20-one 21-acetate.

60. 3-eth0xy-16/3,19-dimethyl-A -IOa-pregnadiene- 17,21-diol-20-one 21-acetate.

61. S-ethoxy-19-ethyl-16a,l7a-isopropylidencdioxy- A -1Oaregnadicn-Z1-ol-20-one acetate.

62. 3-ethoxy-19-ethyl-A fi-IOa-pregnadiene- 17 a,21-diol-20-one 21-acetate.

63 3-ethoxy-16ot-methyl-19-ethyl-A -10a-pregnadiene-17a,21-diol-20-one 21-acetate.

64. 3-ethoxy-16fi-methyl-19-ethyl-A -la-pregnadiene-17a,21 dio1-20-one ZI-acetate.

Example IX A mixture of g. of 3-ethoxy-19-methy1-A -apregnadiene-17a,21-diol-20-one 21-acetate (Cpd. No. 57), 2 g. of anhydrous sodium acetate and 100 cc. of acetone was treated with 32 cc. of water and the solution was cooled to a temperature between 0 and 5 C. There was then added 1.1 molar equivalents of N-chloro-succinimide and 2 cc. of glacial acetic acid and the mixture was stirred between 0 and 5 C for 30' minutes. It was then diluted with water, kept overnight at 0 C. and the precipitate formed was collected, washed with water, dried under vacuum and recrystallized from acetone thus giving 6B-chloro-19-methy1-A -10a-pregnene-17ot,21-diol- 3,20-dione 21-acetate (Cpd. No. 65).

The compounds Nos. 58 to 64, inclusive, were treated by the above method, thus affording respectively:

Example X 1 g. of 3-ethoxy-19-methyl-A -lOa-pregnadiene-17m, 21-diol-20-one 21-acetate (Cpd. No. 57) was dissolved in 25 cc. of dimethylformamide. The solution was cooled to 0 C. and a stream of perchloryl fluoride was passed for 5 minutes; the solution was allowed to come slowly to 20 C.; it was then poured into water and extracted with ethyl acetate. The extract was washed with saturated aqueous solution of sodium bicarbonate, then with water to neutrality, dried over anhydrous sodium sulfate, and evaporated to dryness. By chromatography over washed alumina there was produced 613- fluoro-l9-methyl-N-IOa-pregnene 1704,21 diol 3,20- dione 21-acetate (Cpd. No. 73).

The compounds Nos. 58 to 64, inclusive, were treated by the above method, thus affording respectively:

Cpd. No.:

74. 6,6-fluoro-19-methyl-16a,17a-isopropylidenedioxy-A -1Oa-pregnen-Z1-o1-3,20-dione acetate. 75. 6B-fiuoro-16a,19-dimethy1-A -ltla-pregnene- 17a,21-(liOl-3,ZO-dl0l16 21-acetate. 76. 6/8-fiuoro-16B,19-dimethyl-A -IOa-pregnene- 17a,21-diol-3,20-dione 21-acetate,

1Q Cpd. No.2

' 77. 65-fluoro-19-ethyl-16a,17ot-isopropylidenedioxy- A -10a-pregnen-21-ol-3,20-dione acetate.

78. 6p3-fluoro-19-ethy1-A -10a-pregnene-17a,21-

diol-3,20-dione 21-acetate.

79. 6(3-fluoro-16a-methyl-19-ethyl-A -IOa-pregnene- 17oc,21-diOl-3,20-di0116 21-acetate.

- 80. 6,8-fiuoro-16fl-methyl-19-ethy1-A -IOa-pregnene- 17a,21-diol-3,20-dione 21-acetate.

Example XI The following solutions A, B, and C were prepared using distilled Water as solvent: solution A was prepared by mixing 425 cc. of a 1.74% dipotassic phosphate solution (K HPO with 75 cc. of 1.38% monosodic phosphate; solution B was prepared by diluting a mixture of 1 It. of 4.5% sodium chloride solution, 40 cc. of a 5.75% potassium chloride solution and 10 cc. of a 19.1% magnesium sulfate solution, to a volume of 5 1t. solution C was prepared by dissolving 20.9 g. of fumaric acid and 14.4 g. of sodium hydroxide in 1 it. of water and diluting the solution to 1.2 It. Then 475 cc. of solution A, 4.32 It. of solution B and 1.2 It. of solution C were mixed.

Adrenal glands of recently slaughtered cattle, defatted, were ground in a meat grinder until a homogeneous mass was obtained; to 1 kg. of homogenate was added 2. liters of the mixture of A, B, and C solutions with vigorous stirring. To the mixture there was then added 1 g. of 19- methyl-A -10a-pregnene-17u,21-diol-3,20-dione 21-acetate (Cpd. No. 1) dissolved in 5.30 cc. of propyleneglycol, the mixture was stirred at 28-37 C. for 3 hours, 13 liters of acetone were added and the mass was stirred at room temperature for an additional 1 hour.

The acetone extract was separated by filtration the ground adrenals were washed with 6 liters of acetone, the

extracts were combined and the solvent removed by distillation under reduced pressure. Chromatography on alumina and crystallization of the solid fractions afforded 19-methyl-A -10a-pregnene-11,8,17a,21-triol 3,20 dione 21-acetate (Cpd. No. 81).

The compounds Nos. 2 to 8, inclusive, were treated by the above procedure, thus aifording respectively:

Example XII The compounds Nos. 25 to 56, inclusive, were treated following the procedure described in the foregoing example, thus affording respectively:

Cpd. No.:

89. 6B, 19-dimethyl-A 10'a-pregnene-1 1 5, 17 (1,21-

triol-3 ,20dione.

90. 6/3,l9-dimethyl-16a,17a-isopropylidenedioxy- A4-10oc-PI'6gI16I1fi-1 1/3,21-diol-3,20-dione.

91. 6 3,16a,19-trimethyl-A -IOa-pregnene- 11B, 17a,21-triol-3 ,ZO-dione.

92. 6/3,16,8,19-trimethyl-A -1Ool-pregnene-11,8,17a,21-

triol-3,20-dione.

93 6,B-methyl-19-ethyl-16a,17a-isopropylidenedioxy-A -1 (la-pregnene-l 1 ,B,21-diol-3,20-dione.

11 Cpd. No.2 V

94. 6/3-methyl-19-ethyl-A -lOa-pregnene-l1,8,17a,21- triol'-3,20-dione. w

V 95. 65,16a-dimethyl-I9-ethyLA -IOa-pregnene- Y 11B,17a,21-triol-3,20-dione. v

96. 6B,16,8-dimethyl-19-ethyl-A -1Oa-preghene 11,6,17a,21-triol-3,20-dione.

97. 6oz,19-dimethyl-l9-ethyl-A -10u-pregnene 1lfi,17a,21-triol-3,20-dione.

98. 6a, 19-dimethyl 19-ethyl-1 6a, 17m-is0propylidene dioxy-A -10ot-pregnene-115,21-diol-3 ,20-dione.

1 99. 6m,16a,19-trimethyl-l9 ethyliA -la-pregnene- 115,17a,21-triol-3,20-dione. V

100. 6a,16fl,19-trimethyl-19-ethy1-A -u-pregr1ene- 11,B,17oc,2l-triol-3,20-dione.

101. 6a-methyl-19-ethyl-l6 oc,l7cc-isopropylidenedioxy-A -10o -pregnene-1l/3,21-diol3,20-dione 103. 6a,16oa-dimethyl-19-ethyl-A -10 apregnene- 11}8,17 x,21-trio1-3,20-dione.

104. 6a,1618-dimethyl-19 ethyl-A -10a-pregnene- 1118,17u,21-triol-3,20-dione. V

1 05. 6 t-ch1oro-19-methy1-A -lOa-pregnene- 11,6,17 a,2111iO1-3,20-d10116 ZI-acetate.

106. 6a-chloro-19methyl-16a,17o1-isopropy1idenedioxy-A -10a-pregnene-115,21-(1101-3 ,20-dione ZI-acetate.

107. 6u-ch1oro-16a,19-dimethyl-A -IOaregnene- 11 [1,17 a,21-trio1-3,20-dione ZI-acet'ate.

108. 6a-chloro-165,19-dimethyl-M-IOa-pregnene- 11,8,17m,21-l1iOl-3,20 -di0n6 21-acetate.

109. 60c chloro 19 ethyl 16oz,17oc isopropyl idenedioxy A l0ocpregnene 115,21; diol 3,20 dione ZI-acetate.

110.-6a chloro 19 ethyl A 10a pregnene 115,'17a,21 triol 3,20 dione 21 acetate.

111. 6a chloro -160t methyl 19 ethyl A -10rx pregnene 11,62,170: 21 triol 3,20 dione 21 7 I acetate.

112. 60c chloro 16,6 methyl 19 ethyl A 10a pregnene 1lfi,1 7ec,21 triol 3,20 dione 21 acetate 113. 6oz fluoro 19 methyl A 100a pregnene 11,8,17 1,21 triol 3,20 dione 21 acetate. 114.; 60; fiuoro 19 methyl 16a,17 x isopropylidenedioxy A 10a pregnene 11,8,21 -diol 3,20 dione 21 acetate.

115. 60 fiuoro 1601,19 dimethyl A 10a pregnene 11,8,17co21 -,trio 1 3,20 dione 21 acetate. 7

116. 611'- iluoro 16 6,19, dimethyl A 10cc Erample XIV 5 g.. of 19-rnethyl-A -10a=pregnene-11{3,17x,2l-triol 3,20-dione 21-acetate. (Cpd. No.81) was dissolved with slow heating in 72.5 cc. of dimethylformamide, the mixture was cooled, 2.1 g. of mesyl chloride and 2.5 cc. of pyridine were added and the solution Was kept at 80. C. for half an hour. The reaction mixture was cooled, water was added and the product was extracted with ethyl acetate. The extract was washed with-water, dried over anhydrous sodium sulfate and the solvent was evaporated.

Recrystallization of the residue from acetone-hexane turnished 19 methyl A diol-3,20-dione 21-acetate. I V

2.8 g. of Nrbromoacetamide were added toa mixture 10a pregnadiene 17 x,21

of 5 g. of the latter steroid, cc. of pure dioxane and 0.8 cc. of 0.4 Nfperchlorie acid while stirring in the dark and atroorn temperature during 1 hour. The reaction mixture was stirred 'for 1 hour further,. a solution of 10% sodium suliite Was'then added until the potassiumstarch indicator paper no longer turned blue, ice was added, the mixture was extracted with chloroform and the extract was washed consecutively-With water. aqueous sodium bicarbonatesolution and water, and the solvent was removed by distillation under vacuo. By trit-v uration of the residue with acetone there was obtained the corresponding 9a-bromo-l 1 fi-ol-derivative.

A mixture of 2 g. of anhydrous potassium acetate and 20 cc. of acetone was heated. almost to'boilin'g and then a solution of 1.7 g. of the bromohydrin in 20 cc. of acetone was added slowly while stirn'ng; the mixture was thenrerefluxed for 10 hours, cooled and almost all of the acetone was distilled off; iced-water was then added, the precipitate was filtered, washed with water and dried. Upon recrystallization from methylene chloride-benzene there was obtained 916,115 oxido 19 'nethyl A 100i pregnene 17oc,2l,- diol 3,20 theme 21 acetate (Cpd.

Following exactly the same'procedures, the'compounds Nos. 82 to 136, inclusive, were. successively converted pregnene 11,6,17oc,21 triol 7 3,20 dione 21 118. c;- fiuoroa 19 ethyl A 10a preg nene 11,13,17a,21 triol 3,20 dione 21 acetate. 119. 604 fiuoro 1601 methyl 19 ethyl A -10 acetate. 120. 6oz fluoro 416,8 11161113111519 ethyl A 101a pregnene 115,170.,21 triol 3,20 dione 21 acetate.

' Example XIII The compounds Nosto .80, inclusive, weretreated.

in accordance with the procedure described inExample XI, thus allordingrespective1y: V 1

Cpd. No:

121. 6pchloro- 19 #methyl A 10cc pregnene '11fi,17a,21 triol 3,20 dione- 21 acetate.-

1221.65,- ,chloro 19 methyl 161x170: isopropy Y lidenedioxy A 101x -,pregnene 115,21. l diol Q 3,20 dio'ne 21 acetate.

pregnene- 11 ,171 21 triol 3,20. dione 21 f into the corresponding A "10a pregnadienede rivatives, the corresponding M-9a-br'0mo-11 fi alcohols and then respectively into the following oxido compounds.

Cpd. No.2 i

138. 95,1113 oxido 19 methyl 1601,17a iso propylidenedioxy A 10a 4 pregnen 21 .-.ol 3,20 dione, acetate. a e

139. 9,8,1118 oxido.,- 16a,19 dimethyl .as 100. pregnenee 1712,21 diol 3,20 dione 21 acetate.

14.0. 9 11s oxido 16,3,19 dimethyl- 5 1-100. pregnene 1701,21 diol 3,20 dione. 21E acetate.

141. 9 ,11 oxido 19 ethyl 16 m; isoriropyb idenedioxy A .-10c1 pregnenf 21' ol 3,20

- dione acetate. I a a i V 142'. 96,115 oxido 19 {ethyl A 10a spregnene 17,21 diol 3,20 dione ,21 acetate.

143. 919,115 oxido 16a methyl 19 ethyl A acetate.

I pregnene 17a,'21:.:1 1io1:-* 3,20dione. 146. 9,8,115 OXidO r 65,19 dimethyl 1601,1701 "isopropylidenedioxy9A 10a -.-Zpr .egnen 21 ol' 3,20-dione. j

Example X VIII The compounds Nos.- 105 to 136, inclusive, were treated following the procedure described in Example XVII, thus aifording the-corresponding 3,11,20-trione derivatives.

Example The compounds Nos. 193 to 200, inclusive, Nos. 217 to 256, inclusive and Nos. 273 to 304, inclusive, were treated in accordance with Example XVII, thus yielding the corresponding 3,11,20-trio'ne derivatives.

A mixture of l g. 'of 19-methyl-A -1Oa-pIegnene-I1p, 17u,21-triol-3,20-dione ZI-acetate (Cpd. N0. 81) 2 g. of

chloranil and 50 cc. of ter-butanol was refluxed for 8 The mixture Was cooled, the excess of chloranil,

hours. filtered off and washed with ethyl acetate'and the organic extracts washed with a 'cold aqueous solution' of sodiumhydroxide until the washings were colorless. It

was then dried over anhydrous sodium sulfate and evapoi rated to dryness. Recrystallization from methylene chloride-ether, after decolorization with2 g. of alumina, gave dione 21-acetate (Cpd. N0. 313).

Example XX Following the same procedure disclosed in Example XIX, there were treated the compounds Nos. 82 to 88, inclusive, 'atfordin'g respectively:

Cpd. No.:

314. 19-methyl-16a,17a-isopr0pylidenedioxy- A ,-10d-pregnadie'ne-11fl,21-diol-3,20-dione 21- acetate. 3 15. 16a,19-dimethyl-A -IOwpregnadiene-11,8,

17a,'21'-triol-3,2C-'dione 21-acetate. 316. 16B,1'9-dimethy1-A -1(la-pregnadiene-l 1B,

17a,21-triol-3,20-dione ZI-acetate. 317. l9 ethyl-1611,17a isopropylidenedioxy-M IOa-pregnadiene-l1B,21-dio1-3,20-di0ne 21- acetate. 31 8, 19-ethyl-A -10a-pregnadiene-1 ,B,17oc,21-

trio1-'3,20-di0ne ZI-acetate. 31 9. 16 a-methyl 19-ethy1-A lila-pregnadiene- 11B,17a,21-t1iOi-3,20-di0116,zl acetaie.

3 20. l6fi methyl-19-ethyl-A -1Ompregriadiene- 11 B,17u,21-trio1-3,20 dione 21-acetate.

Example XXI 2.3 Example XXII The compounds Nos. 89' to 136, inclusive, "and Nos. 193 to 304, inclusive, were treated followingthe procedure described in Example XIX, thus afiording the corresponding M' -derivatives. I

Example XXIII A'rnixture of 500mg. of 1 9 methyl-A 4-lOa-pregnene- 11,8,170,21-tri0l-3,20dibrie21aeta1le (Cpd.- N0. 81) 10 cc. of dioxane and 35D of 2,3-dichloro5,6-dicyano 1,4.-benzoquinone was refluxed for IO'hours. It was then cooled, the 2,3 -dichloro-5,6-dicyano 1,4 benzohydroquin'one formed d'urin'g the reaction filtered 01f, "andthe filtrate evaporated to dryness. The residue was'dissolved in acetone and filtered through 10 grof Crystallization from a c'etone-jhexane 'gave v19 r1iethyl-'A ,%-10ozpregnadiened1 3,17a,21 triol-3,20-dione 2l-acetatev (Cp'd. N0. 329).

Following the same procedure, th'erepwe i'e treated the compounds Nos. 82 to 88,'incli1sive,"aifording respectiv'ely: 7

Opd. No.:

330. 19-methyl-16a 12a isopropylidenedioxy-A lOwpregnadiene-l 1 fl,21 d iol-3,'20-dione 21-acetate. 33 1. 1 6 19 -dimethyl -AL 1 Qot-pregnadiene- 1 1B,1-7ot,21 triolr3,20-dione 2 l-acetate. 332. 165,19-dimethylAIf*-10a pregnadiene- 116,17:: ,21-triol-3,20 dione 21-acetate. '3 3'3. 19-ethyI-16a, 17 oi-isobropylidenedioxy-N' 10apregnadiene-d1 3,21-diol 3,20 dione- 21-ac etate. y 1 qsre adiene-1.1p,17m,21-trio1- 3,2Q-dione ZL-acetate, v

335. 1 6 t-methyl 1Q-ethyl-AM IOa-gpregnadiene- H 11,8,17u,21-triol-3,20 dione Ill-acetate. I 336. 16,L 3-In ethy-l -methyl-A 91(hx-pregnacliene- 1 1p,17a,21-triol-3,20-dione 21,-acetate.

Example XXIV The compounds Nos. 305 to 3 12, inclusive, were treated in accordanc-e'with the foregoing example, thus yielding respectively:

Opd. No.:

3:3 7. 19 n1e'thyl-A -1Oaregnadiene 17ot,21-dio1- 3','1:1',20 -trione ZI a-cetate. 338. 19 m'ethyI-16u,17aa-isofiropylidenedioxy-a -10aregnadiemZLoI-B;1'1,-20-trione acetate. 339. 16a,19-dimethy1-A -10bt-pregnadiene-17a,21-

"diol"-3,' 11 ,2O-tiione 21-a'ctate. 340., 16,8,19-diinethyl A ql0d-pregnadi'ene-17a,21-

dio13,1'1,20.-trione 21-aeetate. 341. '19-ethy1=1 6a,17a-isopropylidenedioxya 10apregnadien-21-ol-3J1,20-trione acetate 342. 19-ethyl-A 'i-l-fla pregnadiene-17a,21 diol- 3,1'1,20-tri0ne 21--acetate. i 343. 16oz-methyl-19-ethyl-A -1(la-pregnadiene- :,21-diol 3,11,20 trione 21-ace-tate. 344. 16fifmethyl-l9 ethyl A 10apregnadiene- *17oc,21 -diOl-3,11,20 11Ii0116 21-acetate.

Example -XX V The compounds Nos. 89 to 136, inclusive, and Nos. 193 to 304, inclusive, werew treatedfollowing. the procedure described in Example XXI-II, thus affording the corresponding A f-derivatives.

' EatdmpleXXI l The compounds Nos. 31 3 to 3 2 8, inelusive,were treated in accordance with-Example XXIII, thus furnishing respectively:

Cpd.N 0.:

345. 19 r ne;thyl=A "8 -l tlcupregnatriene-l1 8,17o,21-

trio1-i3,20-dione 21-acetate.

346. l9-methyl-16a,17a-isopropyl-idenedioxy-A 10a-pregnatriene-1-l5,21-diol-3,20-di0ne Zl-acetate.

Cpd. No.2

0.. a2 Example XXIX The compounds Nos. 305 to 312, inclusive, were treated following the procedure of Example XXVIII, thus affording respectively:

347. 160:,19-dimethyl-A -10a-pregnatriene- Cpd,

1 i m' -i ll-acetate- 369. 19-methyl-A -a-pregnene 1701,21 diol 3,11, 348. l65,l9-dimethyl-A -l(la-pre-gnatriene- 20-31 "11l3,\17%2141401330410116 21410611316- 370. 19 methyl 16a,l7a isopropylidenedioxy- 349. 19-ethyl-16a,17a-isopropylidenedioxy-A}' A -10u-pregnen-21-ol-3,1 1,20-trione.

10a-pregnatriene-1 15,-21-dio1-3,20-dione 21-ace- 10 371. 16oc,19 dimethyl A 100a pregnene 17a,21- tate. diol-3,11,20-trione. 350. ll 9-ethyl-A -lOa-pregnatriened15,17a,21- 165,19 dimethyl A4 10a pregnene 1706,21-

triol-3,=20-dione '21-acetate. dicl'3JLzo-tfione- 35L v s h l 9 ethyLAL4,6 1.0a pregnatriene 373. 19 ethyl 1604,170c ISOPI'OPYhdeHedIOXY A4- 115,17a, 2l1-triol-3,20-dione 21-acetate. 'fl 7 1 352. 165-methyl-19-ethyl-A -10a-pregnatrieneidiiigg A pregnene 1 dlo 1 15,17 oc, Z1-t1'iO1-3,20'-dl0n6 2l-acetate. 4 .353. 19-methyl-A1,4,6-1Oa-pre natriene170:,2l-diol- 15153,,82? A Pregnene 331304110116 zl'acetalte' 20 376. 165 methyl 19 ethyl A -10oc pregnene- 17a,21-di01-3,1 1,20-trione.

1()a-pregnat-r-ien-21-ol-3,1'1,2()-trione acetate.

:3 55. 16a,19-dimethyl-A -10a-pregnatriene-17u,2l

dio1-3,11,20-trione 21-acetate.

=356. 165,19dimethyl-A -10a-pregnatriene-17a,21- 25 diol-3,l l,20 trione ZI-acetate.

357. 119-ethyl-l6a,17a isopropylidenedioxy-A 1Oa-pIe'gnatrien-Z1-01-3,11,20-trione acetate.

8. 19-e'thy1-A -lOa-pregnatriene-17a,2l-diol- 3,11,20-trione Zl-acetate.

359. 16a-methyl-19-ethyl-A -10a-pregnatrienet17a,21-diol-3,11,20-trione -21-a-cetate.

2360. 165-methyl-1-9-ethyl-A -lOa-pregnatriene- 1'7a,21-diol-3,1 1, 20-trione 2l-acetate.

Example XXX The compounds Nos. 105 to 136, inclusive, Nos. 193 to 200, inclusive, Nos. 217 to 256, inclusive and Nos. 273 to 304, inclusive, were treated in accordance with Example XXVIII, thus producing the corresponding 21- free alcohols.

Example XXXI 30 The compounds Nos. 313 to 360, inclusive, were treated following the procedure described in Example XXVHI thus yielding respectively: Cpd. N0;

377. 19 methyl A 9- 1004 pregnadiene 115,

17a,21-triol-3,20-dione. 378. 19 methyl l6a,l7oc isopropylidenedioxy- A -l0a-pregnadiene-1l5,21-diol-3,20-dione. 379. 16a,l9 dimethyl A 10a pregnadiene- 115,17a,21-triol-3 ,ZO-dione. 380. 165,19 dimethyl A 10a pregnadiene- 11 5, 17a,2 l-triol-3,20-dione. 381. 19 ethyl 16u,l7a isopropylidenedioxy A lOa-pregnadiene-l l5,2l-diol-3,20-dione. 382. 19 ethyl A 10cc pregnadiene 115,17,

2l-triol-3,2G-dione. 383. 16a methyl 19 ethyl A 1004 pregnadiene-l 15,17a,21-triol-3,20-dione. 384. 165 methyl 19 ethyl A 10a pregnadiene-l15,l7a,21-triol-3,20-dione. 385. 19 methyl A 10a pregnadiene 17a,21-

diol-3,1 1,20-trione. 386. 19 methyl 160:,17a isopropylidenedioxy- A 10a pregnadien 21 ol 3,11,20 trione. 387. 1606,19 dimethyl A 10a pregnadienel7a,2l-diol-3 ,1 1,20-trione. 388. 165,19 dimethyl A 10a pregnadiene- 17a,2l-diol-3,l1,20-trione.

Example XX VII The final compounds of Example YXII were treated in accordance with Example XXIII thus aifording the 49 corresponding A MOuregnatriene derivatives.

Example XX VIII 2 g. of l9-methyl-A -10a-pregnene-115,17a,21-triol-3,20- dione 21-aeetate (Cpd. No. 81) dissolved in 50 cc. of 45 methanol and treated with 5 cc. of a 4% aqueous solution of potassium hydroxide; the reacton mixture was stirred for 1 hour under an atmosphere of nitrogen at 0 C.; the mixture was neutralized with acetic and the methanol distilled under reduced pressure. The residue was triturated with water and the solid collected, washed with water, dried and recrystallized from ethyl acetate methanol, thus producing l9-methyl-A -lOoc-gpregnene- 115,17a,21-triol-3,20-dione (Cpd. No. 361).

Following the same procedure, there were treated compounds Nos. 82 to 88, inclusive, thus yielding respeci l 389. 19 ethyl 160:,170: isopropylidenedioxy A 10a-pregnadien-21-ol-3,11,20-trione. Pd- N0-- 390. 19 ethyl A 10a pregnadiene 1704,21-

362. 19-methyl-16a,17a-isopropylidenedioxy-A loa-pregnene-l15,21-dio1-3,20-di0ne.

diol-3 ,1 1,20-trione. 391. 1600 methyl 19 ethyl A 10a pregnadiene 17a,21-diol-3,l1,20-trione.

392. 165 methyl 19 ethyl A 10o: pregnadiene-l7oc,21-diol-3,11,20-trione.

393. 19 methyl A 10a pregnadiene 115,17a,

21-triol-3,20-dione.

394. 19 methyl 160:,170: isopropylidenedioxy- '395. 160:,19 dimethyl A pregnadiene- 398. 19 ethyl A 10a pregnadiene 115,17a,21-

triol-3,20-dione.

399. 1600 methyl 19 ethyl A 109a pregnadiene-l15,17a,21-triol-3,20-dione.

400. 165 methyl 19 ethyl A 10a pregnadiene-115,17qc,21-triol-3 ,20-dione.

401. 19 methyl A 10oz preguadiene 170;,21-

, diol-3,1l,20-trione. I

402. 19 methyl 16a,17a-isopropylidenedioxy-A lOa-pregnadien-2l-0l3,l 1,20%trione.

403. '16a,19 dimethyl A 10a pregnadiene- 17 ,21- di0l-3,11,20-trione. I k

'404. 165,19 dimethyl A 10a pregnadiene- 170:,2 l-diol-3 ,11,20-trione.

405. 19 -ethyl l6oc,17oc isopropylidenedioxy-A 10a-pregnadien-2l-ol-3,11,20-trione.

"406. 19 ethyl A 10a pregnadiene 1704,21-

diol-3,1l,2O-trio ne.

408. 165 methyl l9 ethyl A 10m pregnadiene-17a,21-diol-3,11,20-trione.

409. 19 methyl 5 A 4 10oz pregnatriene 115,

l7cc,2l-t1'iOl-3,20-di0l'l8.

410. 19 methyl 16a,17oz isopropylidenedioxy- A 1 Oa-pregnatriene-I 15,21-diol-3,2 -dione.

411. 160:,19 dimethyl A1144 10a pregnatriene- 115,17a,21-triol-3,20-dione. I

412. 165,19 dimethyl A 10a pregnatriene- 115,l7a,21-tri0l-3,20-dione. I g

413. 19 ethyl 16a,17u' iSOPIOPYlldCIICdlOXYr'A lOm-pregnatriene-l 15,21-diol-3,20-dione.

414. 19 ethyl A 10oz pregnatriene 115,17,

21-triol-3,20-dione.

415. 160: methyl 19 ethyl A1416 10a pregnatriene-l15,17a,21-tri-01-3,20-dio'ne.

416. 165 methyl l9 ethyl A1416 10a pregnatriene-l15,17a,2l-triol-3,20-dione.

417. 19 methyl A1416 10a pregnatriene 17cc,

21-dio1-3,1 1,20-trione. v

418. 19 methyl 1601,17u isopropylidenedioxy- A -l0a-pregnatrien-2l-ol-3,l1,20-trione. I

419. 160:,19 dimethyl A1415 10oz pregnatriene- 17 oz,21-di0l-3,1 1,2 0-trione. g

420. 165,19 dimethyl A 10a pregnatriene- 17a,21-diol-3,11,20-trione.

421. 19 ethyl 16u,17u isopropylidenedioXy-A 10u-pregnatrien-21-ol-3J1,20-trione.

422; 19-ethyl-A -10a-pregnatriene-17a,2l-diol 3,

1 1,20-trione.

423. 1Gar-methyl-19-ethyl-A 10a pregnatriene- 17rx,2l-diol-3,11,20-trione.

424. 165-methyl-19-ethy1-A 10 pregnatriene- 17u,21-dlOl-3,11,20-11'10116.

Example XXXH ,dione (Cpd. No. 425) The compounds Nos. 90 to 104, inclusive, were treated by the same procedure, thus yielding the corresponding Zl-acetates.

Example XXXIII Upon treatment of compounds Nos. 89 to 104, inclusive,

Example XXXI V 1 g. of l9-methyl l6o ,17u-isopropylidenedioxy A -apregnene-115,21-diol-3,20-diorie 21-acetate (Cpd. ,No. 82) wasv heated .on the 'steambath with cc. of 60% formic acid for 1 hour, cooled, diluted with water-and the precipitate was collected,'washedwith water, dried, and recrystallized from acetone-hexane, thus afiording 19- methyl-A -l0a-pregnene-1 15,1601, 1.7062146111017310 dione 21-acetate (Cpd.No. 426). g I

Following the same procedure," there were treated the compounds Nos. 85, 98, 101, 106,109, 114, and 117, thus aifo'rding respectively:

, tetrol-3 ,20-dione 21-acetate. I H V 428. 6a,19-dimethy1 A 1Oaregnene 115,16a,17a,

21-te trol-3,-20-dione. 7 v

429. '6a-methyl-19-ethyl-A -10a-pregrier1e 115,16u,

17a,21-tetrol-3,20-dione. v

430. 6a-chloro- 1 9-methyl-A -10a pregnene 115,16,

17a,21-tetrol-3,20 dione 21 acetate.

431. 6a-chloro-19 -ethyl-A -10a pregnene 115,1606,

17a,21-tetrol-3,20-dione21-acetate.

432. 6wfluorol9-methyl-A -1O regnene 11,3,16oc,

17a,21-tetrol-3,20-dione21-acetate.

433. 6a-fluoro 19-ethyl A -10 a pre'gnene 115,16a,

17u,21-tetro1-3,20-dione 21-acetate.

Example XXXV The compounds Nos. 194, 197,210, 213, 218, and 22 1, were treated following the procedure described in Example XXXIV, thus afiording respectively:

by the procedure described in Example XXXII, except that acetic anhydride was substituted by propionic anhy dride' and caproic anhydride, there were respectively produced the corresponding 21-propionates and Zl-caproates.

434. 9a-flu0ro-19-methy1-A -1Oa-pregnene 115,16u,

17 a,21-tetrol-3,20-dione ZI-acetate.

435. 9a-fil1O1O196lIl1yl-A -1Goc pregnene 115,160,

17m,21-tetrol-3,20-dione 21-acetate.

436. 9a-fluoro-6a,19-dimethyl-A -10oi-pregnene 115,

16a,17a,21-tetrol-3,20-dione.

438. 6a-chloro-9a-fluoro-19-ethyl-A -10a pregnene- 115,16a,17a,21-tetrol-3,20-dione 21-acetate.

439. 6a-chloro-9a-fluoro-19-ethyl-A -10m '-"pr'egnene- 115,16a,17u,21-tetrol-3,20 dioneill-acetate.

Example XXXVI 'The compounds Nos. 426, 427, 430, 431, 432 and 433, were treated following the procedure of ExampleXXVIII, thus afiording respectively:

Cpd. No.

40. l9-methyl-A -l0a pregnene 115,16u,l7a,21-

- tetrol-3,20-dione.- 41. 19-ethyl-A -lOa-pregnenerl15,16a,17'a,21 tetrol- 3,20-dio11e. 42. 6a-chlor0-19-methyl-A -IOa-pregnene 115,160,

17m,21-t6t1Ol-3,2Q-di0116. 443. 6 t-chloro-19-ethyl-A -1Ooc pregnene 115,16a,

17ct,21-tetrol-3,20-dione; 444. 6o-fluoro-19-methyl-A -IOa-pregnene 115,160,

17a,21-tetro1-3,20-dione. 445. 6a-fluoro-19-ethy1-A -10a --pregnene 115,16a,

17u,21-tetrol-3,20-dione.,

Example XXXVI] The compounds N o's. 426 to 433, inclusive, were treated in accordance 'with the, method of Extreme XXXII, thus. affording respectively: 7 4

Cpd. N0.: 7

446. 19-methyl-:A i-1Oa-pregnenev 1}15,16a,17a,2l-

tetrol-3,20-dione 16,21-diacetate.

447. 9-ethyl-A -10a-pregnene-115,16a,17a,21 tetrol- 3,20-dione 16,21-d'iacet a te.

25 Cpd. No.:

448. 6a,19-dimethyl-A -wot-pregnene 11{3,l6a,17a,

21-tetro1-3,20-dione 16,21-diacetate.

449. 6a-methyl-19-ethy1-A -1Orr-pregnene 11,13,16u,

17a,21-tetrol-3,10-dione 16,21 diacetate.

450. 6u-chloro-19-methyl-A -la-pregnene 11,8,1611,

17a,2l-tetrol-3,20-dione 16,2l-diacetate.

451. u-chloro-19-ethyl-A -10a-pregnene 115,16a,

l7oc,2l-tetrol-3,20-dione 16,2l-diacetate.

452. 6a-fluoro-19-methyl-A -moi-pregnene 1113,160

17a,2l-tetrol-3,20-dione 16,21-diacetate.

453. 6u-fluoro-19-ethyl-A -10a pregnene 11,63,160,

17oc,21-'[8t1O1-3,20-di0116 16,21-diacetate.

Example XXX VIII A solution of 500 mg. of 19-methyl-A -1Out-pregnene- 11,8,16a,17a,21-tetrol-3,20-dione 21-acetate (C-pd. No. 426) in 20 cc. of chloroform was treated with 1 g. of acetaldehyde and a few drops of 3 N perchloric acid and stirred at room temperature for 2 hours. After diluting with water the chloroform layer was separated, washed with aqueous saturated sodium bicarbonate solution and then with water, the chloroform was distilled and the residue was purified by chromatography on neutral alumina, thus yielding 16a,17a-ethylidenedioxy-19-methyl- M-lOa-pregnene-llfi,2l-diol-3,20-dione 21-acetate (Cpd. No. 454).

The compounds Nos. 427 to 445, inclusive, were treated according to the above procedure, yielding the corresponding 16a,17a-ethylidenedioxy compounds.

Example XXXIX A mixture of 1 g. of compound No. 426, 50 cc. of freshly distilled acetophenone and 0.5 cc. of 72% perchloric acid was stirred at room temperature for 1 hour. The resulting mixture was washed with sodium bicarbonate solution and with water to neutrality, then it was steam distilled and the product extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization from acetone-hexane yielded 19-rnethyl-A -moi-pregnene- 1118,16a,17a,21-tetr0l-3,20-dione 21-acetate 16,17-acetophenonide (Cpd. No. 455).

The compounds Nos. 427 to 445, inclusive, were treated according to the above procedure, thus yielding the corresponding 16,17-acetophenonides.

Example XL Into a solution of 3 g. of compound No. 121 in 150 cc. of glacial acetic acid was passed a slow stream of dry hydrogen chloride for 4 hours, while maintaining the temperature around C. The mixture was then poured into ice-Water, the precipitate collected, washed with water, dried and recrystallized from acetone-hexane to give a compound identical with compound No. 105.

I claim:

1. Acompound of the following formula:

where X is a lower alkyl group; W is selected from the group consisting of double bond and a saturated linkage between 0-1 and C-2; Z is a member of the group consisting of hydrogen, a-methyl, p-methyl, a-fluorine, [3- fluorine, a-chlorine and ,B-chlorine; Q is selected from the group consisting of [Ft-hydroxyl and keto; Y is selected from the group consisting of hydrogen, fluorine and chlorine; R is a hydroxyl group; T is a member of the group consisting of hydrogen, a-hydroxy, zit-hydrocarbon carboxylic acyloxy of less than 12 carbon atoms, a-methyl and B-methyl; R and T together are the group wherein R and R are selected from the group consisting of hydrogen and a lower hydrocarbon residue of less than 8 carbon atoms; and R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms.

2. A compound of the following formula:

wherein X is a lower alkyl group; W is selected from the group consisting of a double bond and a saturated linkage between 01 and C-2; Z is a member of the group consisting of hydrogen, methyl, fluorine and chlorine; Q is selected from the group consisting of B-hydroxyl and keto; Y is selected from the group consisting of hydrogen, fluorine and chlorine; R is hydroxyl group; T is a member of the group consisting of hydrogen, a-hydroxy, a-hydrocarbon carboxylic acyloxy of less than 12 carbon atoms, a-methyl and p-methyl; R and T together are the group wherein R and R are selected from the group consisting of hydrogen and a lower hydrocarbon residue of less than 8 carbon atoms; and R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms.

3 19-rnethyl-A- -IOa-pregnene-l1B,17a,21 triol 3,20- dione.

4. 19-methyl-16a,l7u isopropylidenedioxy-A 10apregnene-l 1 B,21-dio1-3,20-dione.

5. 16u,19 dimethyl A IOu pregnene 11fi,l7zx,21- triol-3,20-dione.

6. 165,19 dimethyl A 10oz pregnene 11]3,17oc,21- triol-3,20-dione.

7. 19-ethyl-A mot-pregnene 11,6,17 11-21 triol 3,20- dione.

8. 16u-methyl-19-ethyl A 10a-pregnene-11fi,17u,21-

triol-3 ,20-dione. 

1. A COMPOUND OF THE FOLLOWING FORMULA: 